Emitted dose estimates from Seretide® Diskus® and Symbicort® Turbuhaler® following inhalation by severe asthmatics

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Abstract

The dose emitted from dry powder inhalers may be inhalation flow-dependent. Using an ex vivo method, the Electronic Lung™, we have measured the aerodynamic characteristics of the emitted dose for both active constituents from Seretide® Diskus® (salmeterol xinafoate 50 mcg; fluticasone propionate 500 mcg) and Symbicort® Turbuhaler® (formoterol 6 mcg; budesonide 200 mcg).1 Electronic inhalation profiles were collected from 20 severe asthmatics (mean PEFR 53% predicted) when they inhaled using a placebo Seretide® Diskus® and a placebo Symbicort® Turbuhaler®. These were replayed in the Electronic Lung™ with the respective active inhaler in situ. Mean(S.D.) peak inhalation flow rates (PIFR) through the Diskus® and Turbuhaler® were 94.7(32.9) and 76.8(26.2) l min−1, respectively. From the Electronic Lung™ the Diskus® inhalation profiles provided a mean(S.D.) fine particle dose (FPD) for fluticasone propionate and salmeterol of 20.4(4.8) and 18.4(4.4)% labelled dose. For Turbuhaler® inhalation profiles the FPD was 23.1(12.9) and 20.7(11.1)% labelled dose for budesonide and formoterol, respectively. The linear (p < 0.001) relationships between FPD against PIFR for budesonide and formoterol were 3 (p = 0.002) and 2.8 (p = 0.007) times steeper than fluticasone propionate and salmeterol, respectively. The results highlight a more significant effect of inspiratory flow on variable dosage emission when using the Symbicort® Turbuhaler® compared with the Seretide® Diskus®.

Introduction

Inhalation remains the preferred route of administration for many drugs to treat respiratory disease. However, poor inhaler technique with the pressurised metered dose inhaler may lead to sub-optimal drug delivery (Newman et al., 1991). Dry powder inhalers (DPIs) are inherently breath actuated and have been developed to circumvent these difficulties. They have been formulated so that an aerosolisation force is required for the drug to become available to the lungs. The process of creating a ‘force’ inside the device, to facilitate deaggregation of the powder formulation, depends upon the energy input (inspiratory effort) by the patient and inhaler resistance (Ganderton and Kassem, 1992). The aerodynamic characteristics of the emitted dose provide in vitro data about its potential for deposition in the lungs (Chrystyn, 2003). These aerodynamic characteristics are the fine particle dose and the mass median aerodynamic diameter. It has been shown that for some DPIs the inhalation flow rate has a significant effect on the dose emitted, which is related to the clinical efficacy (Engel et al., 1989, Nielsen et al., 1997, Chrystyn, 2003) and lung deposition (Newman et al., 1991). Additionally, the deposition patterns of aerosolised drugs may be affected by other ventilatory parameters such as the inhaled volume and inhalation flow rates (Martonen and Katz, 1993). To select the most suitable dry powder inhaler for a patient, it would be useful to be aware of the flow rates and the nature of the inhalation profiles that different groups of subjects can generate through various inhalers. This may be particularly important in adults or children with severe asthma who may have less capacity to generate the most desirable inspiratory effort to use different DPIs.

An ex vivo method, using the Electronic Lung™ has been described (Brindley et al., 1994, Burnell et al., 1998a, Burnell et al., 1998b). Use of the Electronic Lung™, an inhalation simulator (Brindley et al., 1994; Burnell et al., 1989a) provides a realistic model of inhaler behaviour by using inhalation profiles collected from patients. The ability of a patient to inhale drug as respirable particles (referred to as the fine particle dose) is assessed by using actual recorded inhalation profiles through each device for subsequent in vitro analysis. The aerosol that the patient's inhalation would have provided can be accurately analysed to look at the proportions of drug available as fine and large particles and how dose emission relates to the patient inhalation flow profiles.

The Electronic Lung™ method has previously been used to determine the dose emission characteristics for different patient inhalation flow rates when they inhaled through a budesonide Turbuhaler® and a fluticasone propionate Diskus® (Bisgaard et al., 1998, Burnell et al., 2001). We have extended the use of this method to combination dry powder inhalers. The aerodynamic characteristics of the dose of drug emitted from two DPIs, the Seretide®/Advair® Diskus® (GlaxoSmithKline), Accuhaler® in the UK, and Symbicort® Turbuhaler® (AstraZeneca) has been characterised using inhalation profiles collected from adults with severe asthma.

Our aim was to determine the ex vivo performance of the combination dry powder inhalers under inhalation conditions that mimic patient use (Bisgaard et al., 1998) rather than determine the emitted dose characteristics using a vacuum pump as recommended by the Pharmacopoeias (USP, 2000). The fine particle dose and the mass median aerodynamic diameter of 50/500 mcg Seretide® Diskus® and 200/6 mcg Symbicort® Turbuhaler® have been determined using this ex vivo method. For the Symbicort® product, the new version of the Turbuhaler® (“Mark 3”) with a lower resistance (Assi and Chrystyn, 2001), than the one (“Mark 2”) used for formulations with single active drugs, was utilised in this study.

Section snippets

Patients

Patients were recruited from the Chest Out-Patient Clinic of the Leeds General Infirmary. Twenty adult patients (inclusion criteria ≥18 years) with a diagnosis of severe asthma who were dry powder inhaler naïve and were prescribed, as required β2-agonist and 800–2000 μg daily of inhaled beclometasone dipropionate or budesonide, or ≥400 μg daily of inhaled fluticasone propionate were recruited. Patients were also required to have a peak expiratory flow rate (PEFR) of 40–60% of their predicted

Patient demographics

Twenty severe asthmatic patients with a mean age of 56.5 years (range 26–74) were recruited and completed the study. Details of demography and inhalation characteristics are shown in Table 1.

Inhalation parameters

Table 1 shows that the PIFRs were faster using the Diskus® than the Turbuhaler®. The mean difference for the PIFRs through the two inhalers was 17.3 l min−1 (95% CI; 10.4, 24.2 l min−1) which was significant (p < 0.001). This tables also shows that the inhaled volume through the two inhalers were similar. The

Discussion

This study demonstrates that adult patients with severe asthma were able to achieve a high inspiratory flow rate through the Diskus® and the Turbuhaler®. The fine particle dose emitted from the Seretide® Diskus® inhaler for both constituent drugs (salmeterol and fluticasone propionate) was relatively consistent irrespective of the patient inhalation profile. In contrast, for the Symbicort® Turbuhaler® inhaler, these characteristics (for both formoterol and budesonide) were more dependent on the

Conclusion

Data from this study clearly indicate a more consistent and reliable dose delivery from the Seretide® Diskus® than the Symbicort® Turbuhaler® to patients with severe asthma regardless of the inhalation profile used by these patients. The lower resistance of the Diskus® makes it easier for patients to generate a sufficient flow for adequate aerosolisation of the dose. The results suggest that the effects of using the Diskus® should be more predictable than those of the Turbuhaler® with each

Acknowledgements

The help of all the staff at Leeds General Infirmary involved with the outpatient clinics of Dr. Pearson is greatly appreciated. Our thanks go to the patients that were invited and to those that agreed to take part. GlaxoSmithKline provided funding for this study and the facilities for the Electronic Lung™. We thank their staff with the co-operation and help when using this equipment. We would also like to thank Diana Jones for her help in preparation of this manuscript.

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    Seretide®, Diskus® and Electronic Lung™ are all registered trademarks of the GlaxoSmithKline group of Companies. Symbicort® and Turbuhaler® are registered trademarks of Astra Zeneca. In-Check Meter™ is a registered trademark of Clement Clark Ltd.

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